Effect of drug dose and timing of treatment on the emergence of drug resistance

BACKGROUND AND

objectivesThere is a significant interest in identifying clinically effective drug treatment regimens that minimize the METHODOLOGY: In a series of experiments, we measured the emergence of atovaquone-resistant mutants of

resultsThe likelihood of high-level resistance emergence increased with atovaquone dose. When varying the timing of treatment, treating either very early or late in infection reduced the risk of resistance. When we varied starting inoculum, resistance was more likely at intermediate inoculum sizes, which correlated with the largest population sizes at time of treatment. CONCLUSIONS AND IMPLICATIONS: (i) Higher doses do not always minimize resistance emergence and can promote the emergence of high-level resistance. (ii) Altering treatment timing affects the risk of resistance emergence, likely due to the size of the population at the time of treatment, although we did not test the effect of immunity whose influence may have been important in the case of late treatment. (iii) Finding the 'right' dose and 'right' time to maximize clinical gains and limit resistance emergence can vary depending on biological context and was non-trivial even in our simplified experiments. LAY SUMMARY: In a mouse model of malaria, higher drug doses led to increases in drug resistance. The timing of drug treatment also impacted resistance emergence, likely due to the size of the population at the time of treatment.